Skin collagen production-promoting agent

ABSTRACT

A problem of the present invention is to provide a skin collagen production-promoting agent without safety problems. Another problem of the present invention is to provide a skin collagen production-promoting food or drink product and a skin collagen production-promoting cosmetic product containing such a substance. TGF-β and/or a TGF-β degradation product, which is acquired by degrading TGF-β with a protease such as pepsin, pancreatin, etc., are used as a skin collagen production-promoting agent or the active ingredient of a skin collagen production-promoting food or drink product and a skin collagen production-promoting cosmetic product. The aforementioned TGF-β and/or TGF-β degradation product have an effect of increasing the collagen content of the skin.

TECHNICAL FIELD

The present invention relates to a skin collagen production-promotingagent, a skin collagen production-promoting food or drink product, and askin collagen production-promoting cosmetic product useful forpreventing skin deterioration such as roughening, wrinkles, and the lossof elasticity in the skin. Particularly, the present invention relatesto a skin collagen production-promoting agent comprising transforminggrowth factor-beta (TGF-β) and/or a TGF-β degradation product acquiredby degrading TGF-β with a protease as an active ingredient.

BACKGROUND ART

As a result of recent advancement in researches on the mechanism of skindeterioration, it has been confirmed that, macroscopically speaking, thefeeling of skin dryness and the roughening of the skin are not onlycaused by the decline of metabolism due to aging but also intricatelyinvolved with the effect of factors such as sunlight (ultraviolet),drying, and oxidation. It has been revealed that collagen fibers, whichare the most primal matrix components of the dermis, are significantlyreduced by the effect of these factors. Wrinkles and sagging of the skinare increased if the machinery for retaining the tension of the skin,such as resilience and elasticity, supported by the collagen fibers isdestroyed due to the effect of the factors such as ultraviolet. Sincecollagen can hold water in molecules thereof and thereby helps to keepthe skin moisturized, if collagen is destroyed by an external factor,the skin is dried and roughened. From the above, a skin collagenproduction-promoting agent is desired that can prevent wrinkles andsagging of the skin by promoting the biosynthesis of collagen, which isone of the major components of the dermic layer, without safetyproblems.

Transforming growth factor beta (TGF-β) is one of the growth factorspresent in the milk of mammals. The TGF-β family includes five subtypes,which are proteins forming a dimer of about 25 kDa by disulfide bonds.The TGF-β family has a function of regulating the promotion/inhibitionof cell proliferation, biosynthesis, differentiation, and apoptosis. Theeffect of inducing differentiation in animal cells has been confirmed asa useful effect of TGF-β (Patent Document 1). TGF-β is also reported asa growth factor of fibroblast cells in the skin (Non-Patent Literature1).

CITATION LIST Patent Literature

Patent Document 1: Japanese Laid-Open Patent Publication No. 2004-254674

Non Patent Literature

Non-Patent Literature 1: J. Dermatol. Sci., Vol. 24 (Supple), p. 70,2000

SUMMARY OF INVENTION Technical Problem

A problem of the present invention is to provide a skin collagenproduction-promoting agent without safety problems. Another problem ofthe present invention is to provide a skin collagen production-promotingfood or drink product and a skin collagen production-promoting cosmeticproduct containing such a substance.

Solution to Problem

As a result of extensive search for a substance producing a skincollagen production-promoting effect contained in various food materialsin order to solve the problems, the inventers found that TGF-β or aTGF-β degradation product acquired by degrading TGF-β increases collagencontent in the skin, thereby completing the present invention.

The present invention includes the following embodiments.

(1) A skin collagen production-promoting agent comprising TGF-β and/or aTGF-β degradation product as an active ingredient.

(2) The skin collagen production-promoting agent of (1), wherein theTGF-β degradation product is acquired by degrading TGF-β with aprotease.

(3) The skin collagen production-promoting agent of (2), wherein theprotease is one or more selected from trypsin, pancreatin, chymotrypsin,pepsin, papain, kallikrein, cathepsin, thermolysin, and V8 protease.

(4) The skin collagen production-promoting agent of any one of (1) to(3), wherein the TGF-β degradation product has an average molecularweight of 500 or more and 8,000 or less.

(5) A skin collagen production-promoting food or drink productcomprising the TGF-β and/or the TGF-β degradation product of any one of(1) to (4).

(6) A skin collagen production-promoting cosmetic product comprising theTGF-β and/or the TGF-β degradation product of any one of (1) to (4).

(7) A method of improving skin quality by oral ingestion of orapplication of TGF-β and/or a TGF-β degradation product.

(8) A method of improving skin quality by oral ingestion of 10 μg perday or more of TGF-β and/or a TGF-β degradation product or applicationthereof at 0.001 to 2 wt %.

(9) A method of promoting production of collagen in the skin comprisingadministering TGF-β and/or a TGF-β degradation product.

(10) The method of promoting production of collagen in the skin of (9),wherein the TGF-β degradation product is acquired by degrading TGF-βwith a protease.

(11) The method of promoting production of collagen in the skin of (10),wherein the protease is one or more selected from trypsin, pancreatin,chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8protease.

(12) The method of promoting production of collagen in the skin of anyone of (9) to (11), wherein the TGF-β degradation product has an averagemolecular weight of 500 or more and 8,000 or less.

(13) A method of preventing or improving skin deterioration comprisingadministering TGF-β and/or a TGF-β degradation product.

(14) The method of preventing or improving skin deterioration of (13),wherein the TGF-β degradation product is acquired by degrading TGF-βwith a protease.

(15) The method of preventing or improving skin deterioration of (14),wherein the protease is one or more selected from trypsin, pancreatin,chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8protease.

(16) The method of preventing or improving skin deterioration of any oneof (13) to (15), wherein the TGF-β degradation product has an averagemolecular weight of 500 or more and 8,000 or less.

(17) A skin deterioration-preventing or -improving agent comprisingTGF-β and/or a TGF-β degradation product as an active ingredient.

(18) The skin deterioration-preventing or -improving agent of (17),wherein the TGF-β degradation product is acquired by degrading TGF-βwith a protease.

(19) The skin deterioration-preventing or -improving agent of (18),wherein the protease is one or more selected from trypsin, pancreatin,chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8protease.

(20) The skin deterioration-preventing or -improving agent of any one of(17) to (19), wherein the TGF-β degradation product has an averagemolecular weight of 500 or more and 8,000 or less.

(21) A skin deterioration-preventing or -improving food or drink productcomprising the TGF-β and/or the TGF-β degradation product of any one of(17) to (20).

(22) A skin deterioration-preventing or -improving cosmetic productcomprising the TGF-β and/or the TGF-β degradation product of any one of(17) to (20).

(23) A method of improving skin quality for purely cosmetic purposes byoral ingestion of or application of TGF-β and/or a TGF-β degradationproduct.

(24) A method of improving skin quality for purely cosmetic purposes byoral ingestion of 10 μg per day or more of TGF-β and/or a TGF-βdegradation product or application thereof at 0.001 to 2 wt %.

Advantageous Effects of Invention

The present invention provides a skin collagen production-promotingagent, a skin collagen production-promoting food or drink product, and askin collagen production-promoting cosmetic product containing TGF-βand/or a TGF-β degradation product as an active ingredient. The skincollagen production-promoting agent, the skin collagenproduction-promoting food or drink product, and the skin collagenproduction-promoting cosmetic product have an effect of promotingcollagen production in the skin and are useful for the prevention andtreatment of wrinkles, sagging, feeling of dryness, and roughening ofthe skin.

DESCRIPTION OF EMBODIMENTS

A feature of the skin collagen production-promoting agent of the presentinvention is that TGF-β and/or a TGF-β degradation product acquired bydegrading TGF-β with a protease is contained as an active ingredient.TGF-β of any origin is usable in the present invention. For example,human- and bovine-derived TGF-βs have gene sequences already revealedand can be produced with gene recombination, and TGF-β produced with agenetic engineering technique is usable in the present invention. TGF-βis contained in a relatively large amount in bovine colostrum and may becollected from the milk. TGF-β is also collectable from the medium ofcell culture and such cell-derived TGF-β is also usable. For example,milk-derived TGF-β is producible in accordance with a known method (see,e.g., J. Protein Chem., Vol. 10, pp. 565-575, 1991), and TGF-β can beacquired from raw milk, powdered milk, skim milk, reconstituted milk, orother processed milk by heat treatment, salting treatment, ethanoltreatment, various chromatographic processes such as ion exchangechromatography and gel filtration chromatography, and an ultrafiltrationprocess in a combined manner as needed.

For the TGF-β degradation product, a peptide mixture is usable that isacquired by limited proteolysis of TGF-β with a protease such astrypsin, pancreatin, chymotrypsin, pepsin, papain, kallikrein,cathepsin, thermolysin, and V8 protease to an average molecular weightof 8,000 or less. Meanwhile, the lower limit of the average molecularweight is preferably equal to or greater than 500. For example, theaverage molecular weight of the TGF-β degradation product is 500 or moreand 8000 or less, 1500 or more and 8000 or less, 2500 or more and 8000or less, 3500 or more and 8000 or less, 4500 or more and 8000 or less,5500 or more and 8000 or less, 6500 or more and 8000 or less, 7500 ormore and 8000 or less, 500 or more and 7500 or less, 1500 or more and7500 or less, 2500 or more and 7500 or less, 3500 or more and 7500 orless, 4500 or more and 7500 or less, 5500 or more and 7500 or less, 6500or more and 7500 or less, 500 or more and 6500 or less, 1500 or more and6500 or less, 2500 or more and 6500 or less, 3500 or more and 6500 orless, 4500 or more and 6500 or less, 5500 or more and 6500 or less, 500or more and 5500 or less, 1500 or more and 5500 or less, 2500 or moreand 5500 or less, 3500 or more and 5500 or less, 4500 or more and 5500or less, 500 or more and 4500 or less, 1500 or more and 4500 or less,2500 or more and 4500 or less, 3500 or more and 4500 or less, 500 ormore and 3500 or less, 1500 or more and 3500 or less, 2500 or more and3500 or less, 500 or more and 2500 or less, 1500 or more and 2500 orless, or 500 or more and 1500 or less.

The skin collagen production-promoting agent of the present invention isorally administered or applied to produce the skin collagenproduction-promoting effect. When the skin collagen production-promotingagent of the present invention is orally administered, the activeingredient, i.e., TGF-β or a TGF-β degradation product may directly beused or may be formulated in a usual manner and used as an oral agentsuch as powders, granules, tablets, capsules, and drinkablepreparations. In the present invention, for example, oral agents such aspowders, granules, tablets, and capsules are formulated in a usualmanner by using excipients such as starch, lactose, sucrose, mannitol,carboxymethylcellulose, corn starch, and inorganic salts. This kind offormulation can be achieved by using the excipients as well aspharmaceutical additives such as binders, disintegrating agents,surfactants, lubricants, fluidity promoters, coloring agents, andflavors as needed. More specifically, binding agents include, forexample, starch, dextrin, gum arabic, gelatin, hydroxypropyl starch,sodium carboxymethyl cellulose, methylcellulose, crystalline cellulose,ethyl cellulose, and polyvinyl pyrrolidone. Disintegrating agentsinclude, for example, starch, hydroxypropyl starch, carboxymethylcellulose, sodium carboxymethyl cellulose, cross-linked sodiumcarboxymethyl cellulose, and crystalline cellulose. Surfactants includesoybean lecithin, sucrose fatty acid ester, etc.; lubricants includetalc, wax, sucrose fatty acid ester, hydrogenated vegetable oil, etc.;and fluidity promoters include anhydrous silicic acid, dried aluminumhydroxide, magnesium silicate, etc.

TGF-β or a TGF-β degradation product may be combined with nutrients,food or drink etc., directly or after formulated into preparations. IfTGF-β or a TGF-β degradation product is contained together with acomponent conventionally considered to be effective in collagenproduction, such as vitamin C, a further skin collagenproduction-promoting effect can be expected. Since TGF-β or a TGF-βdegradation product is relatively stable to heat, raw materialscontaining TGF-β or a TGF-β degradation product can be heat-sterilizedunder the normally used conditions.

When the skin collagen production-promoting agent of the presentinvention is applied, the skin collagen production-promoting agent canbe combined with known normally used components depending on the purposeof use and prepared as various dosage forms such as liquid formulation,solid formulation, and semisolid formulation and preferable compositionsinclude ointment, gel, cream, spray, patches, lotion, powder, etc. Forexample, the skin collagen production-promoting agent of the presentinvention can be mixed with hydrocarbons such as vaseline, stearylalcohol, higher fatty acid lower alkyl ester such as isopropylmyristate, animal oil and fat such as lanolin, polyhydric alcohol suchas glycerin, glycerin fatty acid ester, mono-stearic acid, surfactantssuch as polyethylene glycol, inorganic salt, wax, resin, water, and, ifneeded, preservatives such as methyl parahydroxybenzoate and butylparahydroxybenzoate, so as to produce skin collagen production-promotingcosmetics and pharmaceutical agents.

Although an effective oral administration dose of the skin collagenproduction-promoting agent of the present invention is not constant andis prescribed as needed depending on the drug formulation, theadministration method, the purpose of use, and the age, body weight, anddisease condition of the patient to which the promoter is administered,it was found as a result of animal experiments using rats that the skincollagen production-promoting effect can be expected to be produced byingesting 10 μg per one kilogram of rat body weight or more of TGF-βand/or a TGF-β degradation product. Therefore, according to theextrapolation method, the effect can be expected by ingesting 10 μg peradult human or more of TGF-β and/or a TGF-β degradation product dailyand, thus, TGF-β and/or a TGF-β degradation product may be combined withfood or drink or administered as a medical drug so that this requiredamount can be ensured. The administration can be performed several timesper day in a divided manner as needed.

Although an effective application dose of the skin collagenproduction-promoting agent of the present invention varies depending onthe dosage form, TGF-β and/or a TGF-β degradation product may preferablybe contained to be 0.001 to 2 wt % based on the total dosage of thecomposition to be applied. However, if the composition is diluted uponuse as in the case of bath additives, the contained amount may furtherbe increased.

EXAMPLES

The present invention will hereinafter be described in detail withreference to examples and test examples; however, these examples onlyexemplarily illustrate embodiments of the present invention and thepresent invention is not limited by these examples.

Example 1

After a column packed with 3,000 gram of S-Sepharose was sufficientlywashed with deionized water and 10,000 liter of skim milk was allowed toflow therethrough, the column was sufficiently washed with deionizedwater before elution with a linear concentration gradient of 0.1 to 1.0M sodium chloride. An elution fraction containing TGF-β was fractionatedagain with phenyl-S Sepharose hydrophobic column chromatography. Thisfraction was further sequentially processed by C4 and C8 reverse phasechromatography and gel filtration chromatography in an HPLC system toacquire 412 mg of TGF-β (fraction A). TGF-β acquired in this manner isdirectly usable as the skin collagen production-promoting agent.

Example 2

After 25 mg of the fraction A acquired in Example 1 was suspended in 100ml of water, pancreatin was added at the final concentration of 1% toperform enzyme treatment at 37° C. for 5 minutes to 6 hours. After heattreatment was performed at 90° C. for 5 minutes to inactivate theenzyme, 24 mg of TGF-β degradation products (fractions B, C, and D) wasacquired by lyophilization. The average molecular weights of the TGF-βdegradation products B, C, and D acquired in this manner were about8,000, about 500, and about 300, respectively. The fractions B and C aredirectly usable as the skin collagen production-promoting agent.

Test Example 1

The collagen production-promoting effects of the fraction A acquired inExample 1 and the fractions B to D acquired in Example 2 were examinedby animal experiments using rats. Seven-week-old Wistar male rats weredivided into nine test groups (n=6) consisting of a group administeredsaline (control group), a group administered 10 μg per one kilogram ofrat body weight of the fraction A acquired in Example 1 (A-1 group), agroup administered 100 μg per one kilogram of rat body weight of thefraction A acquired in Example 1 (A-2 group), groups administered 10 μgper one kilogram of rat body weight of the fractions B to D acquired inExample 2 (B-1 to D-1 groups), and groups administered 100 μg per onekilogram of rat body weight of the fractions B to D acquired in Example2 (B-2 to D-2 groups), and each of the rats received oral administrationonce a day with a probe and was fed for 10 days. With regard to thecollagen content in the skin, after treating the dermis of the rats inaccordance with the method of Nimni et al., (see Arch. Biochem.Biophys., p. 292, 1967), hydroxyproline content in the soluble fractionwas measured. Since hydroxyproline is a specific amino acid containedonly in collagen and accounts for about 10% of the total amino acidconstituting collagen, collagen content can be estimated (see RyujiAsano et al., Bio Industory, p. 12, 2001). The results are shown inTable 1.

TABLE 1 Hydroxyproline content (μg/ml) Control group 0.3 ± 0.1  A-1group 0.7 ± 0.1* A-2 group 1.1 ± 0.2* B-1 group 0.6 ± 0.1* C-1 group 0.7± 0.2* D-1 group 0.5 ± 0.1* B-2 group 1.0 ± 0.3* C-2 group 1.1 ± 0.2*D-2 group 0.6 ± 0.2* Each numerical value is a mean ± standard deviation(n = 6). *A significant difference exists as compared to the controlgroup (p < 0.05).

As a result, the hydroxyproline content in the soluble fraction after 10weeks indicated significantly higher values in all the test groups ascompared to the control group. Therefore, it was clarified that TGF-βand a TGF-β degradation product having an average molecular weight of500 or more and 8,000 or less have the skin collagenproduction-promoting effect and are useful as a skin collagenproduction-promoting agent. It was also clarified that the skin collagenproduction-promoting effect is observed when TGF-β and a TGF-βdegradation product are administered in an amount of at least 10 μg perone kilogram of rat body weight.

Test Example 2

The collagen production-promoting effects of the fraction A acquired inExample 1 and the fraction B acquired in Example 2 were examined byexperiments using a human fibroblast cell line [CCD45SK (ATCCRL 1506)collected from the skin of Caucasian women]. The normal human fibroblastcell line was seeded onto a 24-well plate at 4×10⁴ cells/well/0.4 ml byusing a modified Eagle's medium (MEM, 10-101, Dainippon PharmaceuticalCo., Ltd.) containing 10 vol % fetal bovine serum (hereinafterabbreviated as FBS), cultured with 5% carbon dioxide under saturatedwater vapor at 37° C. for 24 hours, and then replaced to a 0.6 vol %FBS-containing MEM medium. The fraction A acquired in Example 1 and thefraction B acquired in Example 2 were added to each well (0.1 vol %final) (n=6) and cultured for 24 hours, and β-aminopropionitrile andtritium-L-proline were then added (50 μg/ml and 1 μCi/ml final,respectively), to acquire culture medium after further culturing for 24hours. From the culture medium acquired in this manner, collagenfractions were fractionated in accordance with the method of Webster etal., (see, Analytical Biochemistry, p. 220, 1979) to measureradioactivity incorporated into the collagen fractions. The same testwas conducted as a control without adding TGF-β and the TGF-βdegradation product. The results are shown in Table 2.

TABLE 2 Collagen production (%) Control 100 ± 3  Fraction A 204 ± 11*Fraction B 215 ± 9*  Each numerical value is a mean ± standard deviation(n = 6). *A significant difference exists as compared to the controlgroup (p < 0.05).

The results indicate that all the groups with TGF-β and the TGF-βdegradation product added exhibited a collagen production-promotingability twice or more greater than the group without the addition ofTGF-β and the TGF-β degradation product (control). Therefore, it wasclarified that TGF-β and a TGF-β degradation product have an effect onthe skin fibroblast cells to promote collagen production and are usefulas a skin collagen production-promoting agent.

Example 3

Skin collagen production-promoting drink having composition shown inTable 3 was manufactured in a usual manner. Flavor of the manufactureddrink was favorable and did not deteriorate after storage for one yearat room temperature, and there was no problem such as precipitation.

TABLE 3 Mixed isomerized sugar 15.0 (wt %) Fruit juice 10.0 Citric acid 0.5 Fraction A (product of Example 1)  0.1 Flavors  0.1 Mineral mixture 0.1 Water Added to a total amount of 100.0

Example 4

Dough having composition shown in Table 4 was prepared, shaped, andbaked in a usual manner to manufacture skin collagenproduction-promoting biscuits.

TABLE 4 Flour 50.0 (wt %) Sugar 20.0 Salt 0.5 Margarine 12.5 Egg 12.5Water 3.5 Mineral mixture 0.8 Fraction C (product of Example 2) 0.2

Example 5

Skin collagen production-promoting agent having composition shown inTable 5 was manufactured in a usual manner.

TABLE 5 Dextrose monohydrate 90.5 (wt %) Mineral mixture 5.0 Fraction A(product of Example 1) 3.0 Sugar ester 1.0 Flavors 0.5

Example 6

Skin lotion having composition shown in Table 6 was manufactured in ausual manner.

TABLE 6 Glycerin  3.0 (wt %) 1,3-butylene glycol  3.0 Polyoxyethylenesorbitan  0.5 monooleate (20 E.O.) Methyl parahydroxybenzoate 0.15Citric acid  0.1 Sodium citrate  1.0 Flavors 0.05 Fraction B (product ofExample 2) 0.05 Purified water Added to a total amount of 100.0

Example 7

Cream having composition shown in Table 7 was manufactured in a usualmanner.

TABLE 7 Liquid paraffin  5.0 (wt %) White beeswax  4.0 Cetanol  3.0Squalane 10.0 Lanolin  2.0 Stearic acid  1.0 Polyoxyethylene sorbitan 1.5 monooleate (20 E.O.) Glyceryl monostearate  3.0 1,3-butylene glycol 6.0 Methyl parahydroxybenzoate  1.5 Flavors  0.1 Fraction A (product ofExample 1)  0.5 Purified water Added to a total amount of 100.0

Test Example 3

The skin lotion acquired in Example 6 and the cream acquired in Example7 were used for a practical use test. Comparison products were used thathad the same compositions as Examples 6 and 7 except that TGF-β and theTGF-β degradation product were removed. Twenty adult women having dryskin with sagging and fine wrinkles recognized on the facial surfaceswere randomly divided into two groups of 10 each (groups E and F) andtwenty women with roughening of skin recognized on the hands wererandomly divided into two groups of 10 each (groups G and H) to apply 2g of the skin lotion of the preset invention to the facial surfaces ofthe group E, 2 g of the skin lotion of the comparison product to thefacial surfaces of the group F, 2 g of the cream of the preset inventionto the fingers of the group and 2 g of the cream of the comparisonproduct to the fingers of the group H, twice a day in a similar mannerto the normal usage condition for 10 days. The results are shown inTable 8.

TABLE 8 Feeling of Roughening dryness of the skin Wrinkles Sagging GroupE ++ ++ ++ + Group F ± ± ± ± Group G ++ + ND ND Group H ± ± ND ND ++: Aprominent improvement effect was observed after application for 10 days.+: An improvement effect was observed after application for 10 days. ±:No improvement effect was observed after application for 10 days (nochange occurred from 10 days ago). ND: Not determined

From Table 8, it was clarified that prominent improvement effects wereexhibited especially for feeling of dryness and roughening of the skinin the groups E and G using the skin lotion of the product of Example 6and the cream of the product of Example 7, as compared to the groups Fand H using the skin lotion and the cream of the comparison products.

1. A skin collagen production-promoting agent comprising TGF-β and/or aTGF-β degradation product as an active ingredient.
 2. The skin collagenproduction-promoting agent according to claim 1, wherein the TGF-βdegradation product is acquired by degrading TGF-β with a protease. 3.The skin collagen production-promoting agent according to claim 2,wherein the protease is one or more selected from trypsin, pancreatin,chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8protease.
 4. The skin collagen production-promoting agent according toclaim 1, wherein the TGF-β degradation product has an average molecularweight of 500 or more and 8,000 or less.
 5. A skin collagenproduction-promoting food or drink product comprising the TGF-β and/orthe TGF-β degradation product according to claim
 1. 6. A skin collagenproduction-promoting cosmetic product containing the TGF-β and/or theTGF-β degradation product according to claim
 1. 7. A method of improvingskin quality by oral ingestion of or application of TGF-β and/or a TGF-βdegradation product.
 8. A method of improving skin quality by oralingestion of 10 μg per day or more of TGF-β and/or a TGF-β degradationproduct or application thereof at 0.001 to 2 wt %.
 9. The skin collagenproduction-promoting agent according to claim 2, wherein the TGF-βdegradation product has an average molecular weight of 500 or more and8,000 or less.
 10. The skin collagen production-promoting agentaccording to claim 3, wherein the TGF-β degradation product has anaverage molecular weight of 500 or more and 8,000 or less.
 11. A skincollagen production-promoting food or drink product comprising the TGF-βand/or the TGF-β degradation product according to claim
 2. 12. A skincollagen production-promoting food or drink product comprising the TGF-βand/or the TGF-β degradation product according to claim
 3. 13. A skincollagen production-promoting food or drink product comprising the TGF-βand/or the TGF-β degradation product according to claim
 4. 14. A skincollagen production-promoting food or drink product comprising the TGF-βand/or the TGF-β degradation product according to claim
 9. 15. A skincollagen production-promoting food or drink product comprising the TGF-βand/or the TGF-β degradation product according to claim
 10. 16. A skincollagen production-promoting cosmetic product containing the TGF-βand/or the TGF-β degradation product according to claim
 2. 17. A skincollagen production-promoting cosmetic product containing the TGF-βand/or the TGF-β degradation product according to claim
 3. 18. A skincollagen production-promoting cosmetic product containing the TGF-βand/or the TGF-β degradation product according to claim
 4. 19. A skincollagen production-promoting cosmetic product containing the TGF-βand/or the TGF-β degradation product according to claim
 9. 20. A skincollagen production-promoting cosmetic product containing the TGF-βand/or the TGF-β degradation product according to claim 10.